Intratracheal GLP-1 receptor agonist treatment up-regulates mucin via p38 and exacerbates emphysematous phenotype in mucus hypersecretory obstructive lung diseases.

Abstract

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that stimulates glucose-mediated insulin production by pancreatic beta cells. It is also associated with protective effects in multiple tissues. GLP-1 receptor is highly expressed in pulmonary tissue, hinting possible pulmonary delivery of GLP-1 drugs. However, little is known about the role of GLP-1 signaling in the lung, especially in mucus hypersecretory obstructive lung diseases. Here, we showed that treatment with exendin-4, a clinically available GLP-1 receptor agonist, up-regulates mucin expression in normal airway epithelial cells and in the lung of normal mice, indicating mucus stimulatory effect of GLP-1 under physiological condition. Exendin-4 also increased mucin expression in in vitro cellular and in vivo murine models of obstructive lung diseases via the activation of p38 MAP kinase. Notably, mucin induction in vivo exacerbated key pulmonary abnormalities including emphysematous phenotypes, implying that GLP-1 signaling in the lung is detrimental under pulmonary obstructive condition. Another GLP-1 receptor agonist liraglutide had similar induction of mucin. Together, our studies not only demonstrate novel physiological and pathological roles of GLP-1 in the lung but may also caution against the clinical use of inhaled GLP-1 receptor agonists in the patients with obstructive lung diseases.

• Authors: Hirofumi Nohara, Ryunosuke Nakashima, Shunsuke Kamei, Haruka Fujikawa, Keiko Ueno-Shuto, Taisei Kawakami, Yuka Eto, Mary Ann Suico, Jian-Dong Li, Hirofumi Kai, Tsuyoshi Shuto
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 524 Issue 2 Pg. 332-339 (04 02 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 31996306 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Mucins
• Exenatide
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Cell Line
• Enzyme Activation (drug effects)
• Exenatide (adverse effects, therapeutic use)
• Glucagon-Like Peptide-1 Receptor (agonists, metabolism)
• Hypoglycemic Agents (adverse effects, therapeutic use)
• Lung Diseases, Obstructive (drug therapy, genetics, metabolism, pathology)
• Mice, Inbred C57BL
• Mucins (genetics, metabolism)
• Up-Regulation (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)